MARIK 2017: Vitamin C, Hydrocortisone, and Thiamine in Sepsis (2017)

“Our results suggest that the early use of intravenous vitamin C, together with corticosteroids and thiamine, are effective in preventing progressive organ dysfunction, including acute kidney injury, and in reducing the mortality of patients with severe sepsis and septic shock.”

— The Marik et al. Study Group

1. Publication Details

  • Trial Title: Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study.
  • Citation: Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest. 2017;151(6):1229-1238. doi:10.1016/j.chest.2016.11.036.
  • Published: June 2017, in Chest.
  • Author: Paul E. Marik, M.D.
  • Funding: Not specified.

2. Keywords

Sepsis, Septic Shock, Vitamin C, Ascorbic Acid, Corticosteroids, Hydrocortisone, Thiamine, Organ Dysfunction.

3. The Clinical Question

In adult patients with severe sepsis or septic shock (Population), does treatment with a combination of intravenous vitamin C, hydrocortisone, and thiamine (Intervention) compared to a historical control group receiving standard care (Comparison) reduce hospital mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Sepsis involves a complex interplay of inflammation, oxidative stress, and metabolic derangements. Corticosteroids were known to have anti-inflammatory effects, while vitamin C and thiamine were thought to have antioxidant and metabolic benefits that could be synergistic.
  • Knowledge Gap: There was no clinical evidence to support the use of this specific combination of therapies for septic shock. The study was prompted by the lead author’s clinical experience with a series of cases.
  • Proposed Hypothesis: The authors hypothesized that the early administration of intravenous vitamin C, hydrocortisone, and thiamine would reduce organ injury and mortality in patients with severe sepsis and septic shock.

5. Study Design and Methods

  • Design: A retrospective, single-center, observational, before-after study. This was not a randomized controlled trial.
  • Setting: A single general ICU in Norfolk, Virginia, USA.
  • Trial Period: The control group was treated between June 2015 and December 2015. The intervention group was treated between January 2016 and July 2016.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with a diagnosis of severe sepsis or septic shock and a procalcitonin level >2 ng/mL.
    • Exclusion Criteria: Age <18 years, pregnancy, or limitations on care.
  • Intervention: The “Marik Protocol”: Intravenous vitamin C (1.5 g every 6 hours), hydrocortisone (50 mg every 6 hours), and thiamine (200 mg every 12 hours) for 48 hours or until ICU discharge.
  • Control: A retrospective control group of patients treated with standard care at the same ICU before the intervention was introduced.
  • Management Common to Both Groups: All patients received standard sepsis care according to the Surviving Sepsis Campaign guidelines.
  • Power and Sample Size: No formal power calculation was performed. The study included two consecutive cohorts of 47 patients each.
  • Outcomes:
    • Primary Outcome: Hospital mortality.
    • Secondary Outcomes: Included duration of vasopressor support, need for renal replacement therapy, and change in organ failure (SOFA) scores.

6. Key Results

  • Enrollment and Baseline: 94 patients were included (47 in the intervention group, 47 in the control group). The groups were similar at baseline, though the intervention group had a slightly higher mean APACHE IV score.
  • Trial Status: The observational study was completed as planned.
  • Primary Outcome: Hospital mortality was dramatically lower in the intervention group compared to the control group (8.5% vs 40.4%; P<0.001).
  • Secondary Outcomes: The duration of vasopressor support was significantly shorter in the intervention group. No patient in the intervention group developed progressive organ failure or required renal replacement therapy.
  • Adverse Events: No adverse events related to the intervention were reported.

7. Medical Statistics

  • Analysis Principle: A comparison of two sequential cohorts.
  • Statistical Tests Used: Outcomes were compared using chi-square tests and t-tests.
  • Primary Outcome Analysis: The proportion of deaths in the hospital was compared between the two groups.
  • Key Statistic(s) Reported: Hospital mortality: 4/47 (8.5%) in the intervention group vs 19/47 (40.4%) in the control group; P<0.001.
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: RR = 8.5% / 40.4% = 0.21.
      • Clinical Meaning: An RR of 0.21 means there was a 79% lower relative risk of death in the intervention group compared to the control group.
    • P-value:
      • Calculation: The reported p-value was <0.001.
      • Clinical Meaning: The p-value of <0.001 is far below the conventional threshold of 0.05, indicating a highly statistically significant association.
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group).
      • Calculation: ARR = 40.4% – 8.5% = 31.9%.
      • Clinical Meaning: In this study, for every 100 patients treated with the intervention, about 32 fewer died in the hospital.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR.
      • Calculation: NNT = 1 / 0.319 = 3.1.
      • Clinical Meaning: In this study, approximately 3 patients needed to be treated with the intervention to prevent one additional hospital death.
  • Subgroup Analyses: Not performed.

8. Strengths of the Study

  • Physiologic Rationale: The study tested a novel combination therapy based on a plausible, multi-faceted pathophysiologic rationale.
  • Large Effect Size: The observed difference in mortality was extremely large.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study’s design is its most significant limitation. As a small, single-center, retrospective, before-and-after study, it is at extremely high risk of bias. Unmeasured changes in practice or patient populations between the two time periods (confounding) could account for the entire observed effect. This is not randomized evidence.
  • External Validity (Generalizability): As a single-center study, the results are not generalizable.
  • Other: The study tested a “bundle” of three drugs, making it impossible to know if any single component was responsible for the effect. The mortality rate in the control group was high.

10. Conclusion of the Authors

“The introduction of a protocol of early intravenous vitamin C, together with corticosteroids and thiamine, was associated with a significant reduction in mortality and prevention of progressive organ dysfunction in patients with severe sepsis and septic shock.”

11. To Summarize

  • Impact on Current Practice: This study was one of the most controversial and widely debated critical care papers of the last decade. Its shockingly positive results generated immense interest and led to the widespread, off-label adoption of the “Marik Protocol” in some ICUs. However, due to its major methodological flaws, it did not change formal guidelines. Its main impact was to provide a powerful, hypothesis-generating signal that spurred a massive wave of high-quality randomized controlled trials to test the intervention properly.
  • Specific Recommendations:
    • Patient Selection: For adult patients with severe sepsis or septic shock.
    • Actionable Intervention: This study does not provide sufficient evidence to recommend this protocol. The findings require confirmation in RCTs.
    • Expected Benefit: A potential, but unproven, dramatic reduction in mortality.
  • What This Trial Does NOT Mean: This trial does NOT prove that the vitamin C cocktail is effective. The before-and-after design cannot establish causality.
  • Implementation Caveats: The use of this protocol outside of a clinical trial was not supported by high-quality evidence at the time of its publication.

12. Context and Related Studies

  • Building on Previous Evidence: This study was largely based on basic science and a small preceding study on vitamin C in sepsis by Fowler et al.
  • Influence on Subsequent Research: This study was the direct impetus for numerous large, multicenter RCTs, including VITAMINS (2019), CITRIS-ALI (2019), VICTAS (2019), and LOVIT (2022). None of these subsequent, higher-quality trials were able to replicate the dramatic mortality benefit seen in this original observational study.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: Does the combination of vitamin C, thiamine, and hydrocortisone have any true benefit in septic shock?
  • Future Directions: The large RCTs that followed this study have largely shown no mortality benefit, effectively refuting the original hypothesis. Future research may focus on specific subgroups or different dosing regimens, but widespread enthusiasm has waned significantly.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was highly relevant, testing a novel, inexpensive combination therapy for a common and lethal condition.
  • Methods: The study design (retrospective, before-and-after) is a major limitation and is considered low-quality evidence, highly susceptible to bias and confounding. It is not a randomized trial.
  • Results: The reported effect size was implausibly large, which should always raise skepticism, particularly from a non-randomized study.
  • Conclusions and Applicability: The authors’ conclusion of an association is technically correct, but the strong implication of causality is not supported by the study design. The results are best viewed as a hypothesis-generating case series that required, and subsequently received, rigorous testing in RCTs, which ultimately did not confirm the findings.

16. Disclaimer and Contact

This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.

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